Process of nitrosating aromatic alkyl ketones



Patented July 1, 1941 PROCESS OF NITROSATING AROMATIC ALKYL KETONES Walter H. Hartung, Baltimore, Md., and Frank S.

Crossley, Philadelphia, Pa., assignors to Sharp & Dohme, Incorporated, Philadelphia, Pa., a

corporation of Maryland No Drawing. Application March 24, 1938, Serial No. 197,896

12 Claims. (Cl. 260566) This invention relates to a process for nitrosating aromatic alkyl ketones such as the phenyl-, naphthyl-, substituted phenyl-, and substituted naphthyl-alkyl ketones which are more generally employed for preparing the aromatic alpha- ,oximinoalkyl ketones.

Heretofore aromatic alkyl ketones were nitrosated by introducing an oximino group at the alpha carbon of the alkyl group thereof, and without nitrosating the aromatic nucleus, by dispersing such a ketone (in solution or suspension) in ether and adding a freshly distilled alkylnitrite to the dispersion while bubbling dry hydrogen chloride gas through the reaction mixture. This method was exceedingly costly because of the very expensive reagents employed, the losses resulting from the nature of the reaction and further due to the ready decomposition of the alkyl nitrites, and the general incompleteness of the reaction, and the relatively large reaction volume for a given amount of initial ketone. At the same time this method was inherently dangerous because of the necessity of handling a highly reactive and inflammable mixture containing large quantities of ether and other constituents requiring the exercise of extreme caution to avoid the foaming .or boiling over of the reaction mixture with the attending dangerous results.

It is, therefore, an object of this invention to effect the nitrosation of aromatic alkyl ketones avoiding the use of highly inflammable and explosive solvents such as ether and without employing highly unstable nitrosation agents such as the alkyl nitrites.

oximinoalkyl ketones, both from the consideration of time and reagents employed.

A further object is to provide a method of ni- .35 Another object is to introduce a relatively more i *economical method of producing aromatic alpha trosating aromatic alkyl ketones, whereby larger amounts of the initial ketone may be nitrosated at one time in a given volume, thereby increasing the production capacity of the equipment many times.

' Still another object is the development of a method of nitrosating aromatic alkyl ketones whereby substantially little, if any, unreacted ketone is left at the end of the process.

Other objects will appear from the following detailed description of the invention.

In general, the invention involves treating the aromatic alkyl ketone starting material with an inorganic nitrite capable of reacting to give off nitrous acid under the reaction conditions, wi h an inorganic chloride capable of reacting to give oif hydrogen chloride under the reaction conditions, together with sulfuric acid. The reaction is preferably carried out by diSSolving or dispersing the ketone in a desirable amount of a suitable alcohol solvent and suspending thev inorganic chloride therein. It is also desirable to include, in the reaction mixture at small amount, usually a very small amount, ofhydrochloric acid solution, preferably concentrated, to promote an earlier smoother initiation of the reaction. Better results are obtained when the reaction mixtureis suitablyaeitated. It is d sirable t a d es furic acid gradually or in such ,mannera to prevent the temperature of the reaction mixture from rising so high as to cause undesirable side reactions. While the sulfuric acid should be gradually added to the reaction mixture as just set forth, the whole of the required amount of the inorganic nitrite may be added at once at the beginning, or preferably also in portions. After the required amounts of nitrite and sulfuric acid have been added to the reaction mixture, it is beneficial to continue the agitation for a time of perhaps several hours to insure completion of the reaction. The mixture may then be permitted to stand over night, after which the end product can be purified by simply washing with water, or further purified, if desired, by recrystallization.

The aromatic alphaoximinoalkyl ketones prepared by the process of the invention are valuable as intermediates for the production of the corresponding amino alcohols many of which havebeen found to have valuabletherapell ic properties.

The invention may be illustrated by, although not restricted to,the following example:

Phenyl alphaoximinoethyl ketone ,(alpha oximinopropiophenone or isonitrosopropiophenone) is prepared from propiophenone as follows: Into manner hereinafter describeda total of 38 parts (0.55 mol) of sodium nitrite and 64' parts (0.65 mol) of concentrated sulfuric acid. First 9.5 parts, or one-quarter of the total required amount, of sodium nitrite is added. and then 16 additionof the first quarter of the required sul-.

furic acid, thirty minutes are allowed to elapse and a second one-quarter of the total required quantity of sodium nitrite followed by a second one-quarter of the total required quantity of the sulfuric acid is added in the manner and with the time interval previously described. Then the third one-quarter of the total required quantity of the sodium nitrite and of. the sulfuric acid is added in the same manner. The last one-quarter of each of these reagents is then added except.

that the addition of the last one-quarterof sul-v conditions.

furic acid is extended over a period of sixty minutes, after which the agitation of the reaction mixture .is continued for about three hours. Afterstanding fover night at room temperature, a .solidQmass of crystalsof phenyl alphaoximino- 'ethylkketoneformsr .The product, after recrystallization from toluene melts at 113C; to 114.5 LG Yieldsof at least,85%95% of the end product;"basd'lon thjpropiophenonie are obtained. rrriese .results'indi'cate that the reaction proceeds 'so farLtowardscompletion as to. leave practically no. reacted, propiophenonej to be 7 separated and recovered. J. j. .5

In the.lexamp1 the addition of the sodium nitritefliand sulfuric'. acid;was controlled. as described'inorderto maintain the temp'eraturelof .the .reactioninixture within" the range indicated. .Theftem'peraturemay be permitted .to go-as high as 60?..C, beforeQ-the reaction may become too }vigorous,.but it .is-preferable that it should not be.permittedtoexceed409C. to 50". C. The above described .mannerand timing of the addition of the nitrite. and sulfuric acid maybe varied to shorten the time required by external cooling or othenmeans of cooling by indirect heat removal..

5, According'to. theprocess. of ,-the invention the following-ketones have been. converted into their .respective alpha-,oximino derivatives, having the .respective Q melting; points 1 shown:

. at h 7 alpha oximino r derivative in-Nitropropiephenonen 158-159 p-Chloropropmpl enoner 118 'p-Hydroxybutyrophenone 155 p-Methoxyproplophenone. 120-121 Valerophenoue 65.5-67

f 'lle. invention may be carried lou-t onga, .wide.,. varie ty' of aromatic alkyl ,k t neis,.JIheQaromatic,radical in. such aromatic alkylj, k'etones. employed. as starting materials in theflprocess of-the invention. may be either the hydrocarbon or substitutedhydrocarbon radical, such as ,the-phenyl or substituted phenyl-alkyl for the corresponding oximino ketones, of which R. of the general formula equals six or more may be made by this process. The term aromatic employed in the claims to describe one of the radicals of the ketones concerned inrthe invention shall be construedto be an aromatic radical selected from the group consisting of phenyl, substituted phenyl, naphthyl, and substituted naphthyl radicals.

Any inorganic nitrite capable of giving off nitrous acid upon treatment with a stronger acid such as sulfuric acid, may be employed. Any such suitable nitrite is referred to in the appending claims as an inorganic nitrite capable of reacting to give off nitrous acid under the reaction Particularly good results are obtained when using the alkali type nitrites such as the alkali metal nitrites and the alkaline earth metalhitrites because of their solubility in water and. to a reasonable degree in alcohols.- Examples of such suitablenitrites aresodium nitrite, potassium nitrite, calcium nitrite, magnesium V nitrite, barium nitrite,.and thelike.

. alcohol mentioned,

, action mixturelin this invention arethose from ketones, or the naphthylor. substituted naphthyl-ealkyl. ketones; and v the like. Thus the ketones suitable as initial materials may be representedbyfth'e general formula XAr.CO.CH2R.

infwhichnr is ,theiaromatic radical or residue i.o f,.which.IX;may;be "eitherhydrogen .or one or ,more lsubstituent radicals'selected from the class jgconsisting; "of vhalo enghy ro v. alk xy. nitro chloride to giveloff hydrogen chloride... a

" hich it is generally. possible preparealkyl nitrites; I e 'Qjf. Inplace of thescdiunibhlo'ride describedlin the example, any other, suitable inorganicfchloride capable of reacting under the reaction conditions toliberate hydrogen chloride may. be employed. The chlorides]moreQreadily applicable in the process are thealkaliity pe chlorides, .comprising thechlorides of the alkali metals and also of the alkaline earth metals, such as. sodium or potassium chloride, oncal'cium or magnesium chloride. Thesulfuric acid may be replaced by any other suitable acid capable of 'reacting'with the nitrite to give of? nitrous acid ,and with the The process of the in' ention isparticularly at. tractive from a commercial standpoint because it avoids the cumbersome and incohvenieritpreparation of unstable..,substances.. In ,.thisnew method there is also avoided ext'endedzlaborkand timein the. recovery of the. end product for the desired product is obtained as a. crystalline solid requiring for purification only; the simple-step of washing with water. to-;remove inorganicsalts, after which, if desired, the ..product;may be. fur-.. ther purified bycrystallization from asuitable inert solvent such astoluene or benzine,,preceded, if desired, by intermediate filtration. According to the invention the process can now be-carried outwith many times,; for example,- as many as six to eight times, the originalcharge of ketone in the reaction vessel than-was possible by prior methods. Furthermore, the productive capacity (in-desired end product) of the. equipment is further increased by virtue 'of' the fact that the -ments of it, it is understood that manyalte raftions or modifications thereof may be made without; departing fromjthe spirit of theinventibn which is to be restricted'only to the scope of the appending claims .as limited by the prior art.

We claim:

1: The method of nitrosating aromatic alkyl ketones, in which the aromatic radical isselected from the class consisting of radicals of the phenyl and the naphthyl series, at the alpha carbon of thealkyl group which comprises treating an arcmatic alkyl ketone'with an inorganic nitrite capableof reacting to give off nitrous acid under the reaction conditions, with an inorganic chloride capable of reacting to give off hydrogen chloride under the reaction conditions, together with sulfuric acid.

2. The method ofnitrosating aromatic alkyl ketones, in which the aromatic radical is selected from the class consisting 'of radicals of the phenyl and the naphthyl series, at the alpha carbon of the alkyl group which comprises treat;

ing an aromatic alkyl ketone in the presence of an alcohol selected from the class consisting of the alkyl and phenyl-lower alkyl alcohols and from which it is possibleto prepare an alkyl nitrite, with an inorganic nitrite capable of reacting to give off nitrous acid under the reaction conditions, with an inorganic chloride capable of reacting to give oif hydrogen chloride under the reaction conditions, together with sulfuric acid.

3. The method of nitrosating aromatic alkyl ketones, in which the aromatic radical is selected from the class consisting of radicals of the phenyl and the naphthyl series, at the alpha carbon of the alkyl group which comprises treating an aromatic alkyl ketone in the presence of an alcohol selected from the class consisting of the alkyl and phenyl-lower alkyl alcohols and from which it is possible to prepare analkyl nitrite, and in the presence of a relatively small amount of hydrochloric acid solution with an inorganic nitrite capable of reacting to give off nitrousacid under the reaction conditions, with an inorganic chloride capable of reacting to give off hydrogen chloride under the reaction conditions, together with sulfuric acid.

4. The method of nitrosating aromatic alkyl ketones, in which the aromatic radical is selected from the class consisting of radicals of the phenyl and the naphthyl series, at the alpha carbon of the alkyl group which comprises treating an arcmatic alkyl ketone in the presence of an alcohol selected from the class consisting of the alkyl and phenyl-lower alkyl alcohols and from which it is possible to prepare an alkyl nitrite, and in the presence of a relatively small amount of hydrochloric acid solution with an inorganic nitrite capable of reacting to give oil" nitrous acid under the reaction conditions, with an inorganic chloride capable of reacting to give off hydrogen chloride under the reaction conditions, together with sulfuric acid, and agitating the reaction mixture.

5. The method of nitrosating aromatic alkyl ketones, in which the aromatic radical is selected from the class consisting of radicals of the phenyl and the naphthyl series, at the alpha carbon of the alkyl group which comprises treating an aromatic alkyl ketone in the presence of an alcohol selected from the class consisting of the alkyl and phenyl-lower alkyl alcohols and from which it is possible to prepare an alkyl nitrite, and in the presence of an inorganic chloride capable of reacting to give off hydrogen chloride under the reaction conditions and of a relatively small amount of hydrochloric acid solution by gradually adding an inorganic nitrite capable of reacting to give off nitrous acid under the reactionoon ditions and gradually addingsulfuric acid to the a reaction mixture. 1

6.'The method of nitrosating aromatic alkyl ketones, in which the aromatic radical is selected from the class consisting of radicals of the phenyl and the naphthyl series, at the alpha carbon of the alkyl group which comprises treating an arcmatic alkyl ketone in the presence of an alcohol selected from the class consisting of the alkyl and phenyl-lower'alkyl alcoholsand from which it is possible to prepare an alkyl nitrite, and in the presence of an inorganic chloride capable of .reacting to give off hydrogen chloride under the reaction conditions and of a relatively small amount of hydrochloric acid by adding, in portions of the total required amount, an inorganic nitrite capable of reacting to give off nitrous acid under the reaction conditions and; in portions of the total required amount, adding sulfuric acid to the reaction mixture.

7. The method of preparing aromatic alphaoximinoalkyl ketones, in which the aromatic radical is selected from the class consisting of radicals of the phenyl and the naphthyl series, which comprises treating an aromatic alkyl ketone in the presence of an alcohol selected from the class consisting of the alkyl and phenyl-lower alkyl alcohols and from which it is possible to prepare an alkyl nitrite, and in the presence of an organic chloride capable of reacting to give off hydrogen chloride under the reaction conditions and of a relatively small amount of hydrochloric acid solution, by alternately adding to the reaction mixture separate portions of the total required amount of an inorganic nitrite capable of reacting to give off nitrous acid under the reaction conditions and of the total required amount of sulfuric acid and permitting an appreciable time to elapse between the completion of the addition of a portion of sulfuric acid to the commencement of the subsequent addition of the nitrite, the addition of the separate portions of the nitrite and of the sulfuric acid being so timed that the reaction mixture is maintained throughout the entire process at a temperature below about 60 0., allowing the reaction mixture to cool after the last addition of sulfuric acid and separating the aromatic alphaoximinoalkyl ketone.

8. The process as in claim 7, in which the reaction mixture is agitated throughout the process until solidification takes place.

9. The method of preparing aromatic alphaoximinoalkyl ketones, in which the aromatic radical is selected from the class consisting of radicals of the phenyl and the naphthyl series, which comprises treating an aromatic alkyl ketone in the presence of an alcohol selected from the class consisting of the alkyl and phenyl-lower alkyl alcohols and from which it is possible to prepare an alkyl nitrite, and in the presence of an inorganic chloride capable of reacting to give off hydrogen chloride under the reaction conditions, and while agitating the reaction mixture throughout the entire process, by alternately adding to the reaction mixture separate portions of the total required amount of an inorganic nitrite capable of reacting to give off nitrous acid under the reaction conditions and of the total required amount of sulfuric acid and permitting an appreciable time to elapse between the completion of the addition of a portion of sulfuric acid to the commencement of the subsequent addition of the nitrite, the addition of the separate portions throughout the entire process at a temperature below about 60 0., allowing the reaction mixture to cool after the last addition of sulfuric acid and separating thearomatic alphaoximinoalkyl ketone.

10. The method of preparing aromatic alphaoxim'inoalkyl ketones, in which the aromatic radical is selected from the class consisting of radicals of the phenyl and the naphthyl series, which comprises treating an aromatic alkyl ketone in the presence of an alkylalcohol from which it is possible to prepare an alkyl nitrite, with an inorganic nitrite capable of giving off nitrous acid under the reaction conditions, with an inorganic chloride capable of reacting to give off hydrogen chloride under the reaction conditions, together with sulfuric acid. v V

11. The method of preparingaromatic alphaoximinoa'lkyl ketones, in which the aromatic radical is selected from'the class consisting of radicals of the phenyl and the naphthyl series, which comprises treating an aromatic alkyl ketone in the presence of an alcohol of the lower alkyl phenyl series with 'an'inorganic nitrite capable of giving off nitrous acid under the reaction conditions, with an inorganic chloride capable of reacting to give off hydrogen chloride'under the reaction conditions, together with sulfuric acid.

12'. The method of preparing aromatic alphaoximinoalkyl ketones, in which the aromatic radical is selected from the class consisting of radicals of the phenyl and the naphthyl series, which comprises treating an aromatic alkyl ketone in the presence of an alcohol selected from the group consisting of alkyl and phenyl-lower alkyl alcohols and from which it is possible to prepare an alkyl nitrite, with an inorganic nitrite capable of reacting to give ofi nitrous acid under the reaction conditions, with an inorganic chloride capable of reacting to give off hydrogen chloride under the reaction conditioning, together with sulfuric acid, and so proportioning and timing the addition of the nitrite andof the sulfuric acid in such manner that the reaction mixture is maintained at a temperature below about 60 C. a

WALTER H. HARTUN G. FRANK S. CROSSLEY. 

